JPS59511B2 - Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide - Google Patents
Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfideInfo
- Publication number
- JPS59511B2 JPS59511B2 JP49067656A JP6765674A JPS59511B2 JP S59511 B2 JPS59511 B2 JP S59511B2 JP 49067656 A JP49067656 A JP 49067656A JP 6765674 A JP6765674 A JP 6765674A JP S59511 B2 JPS59511 B2 JP S59511B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- hydroxy
- compound
- grams
- disulfide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- ALTXHLKIALGWNW-UHFFFAOYSA-N 5-ethenyl-4-[[(5-ethenyl-3-hydroxy-2-methylpyridin-4-yl)methyldisulfanyl]methyl]-2-methylpyridin-3-ol Chemical compound CC1=NC=C(C=C)C(CSSCC=2C(=CN=C(C)C=2O)C=C)=C1O ALTXHLKIALGWNW-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 7
- 239000012670 alkaline solution Substances 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- -1 thio compound Chemical class 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UMCWPPXEAJDPDG-UHFFFAOYSA-N 5-ethenyl-2-methyl-4-(sulfanylmethyl)pyridin-3-ol Chemical compound CC1=NC=C(C=C)C(CS)=C1O UMCWPPXEAJDPDG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000002019 disulfides Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- INXPFKKUKYNUFA-UHFFFAOYSA-N 4-(chloromethyl)-5-ethenyl-2-methylpyridin-3-ol;hydrochloride Chemical compound Cl.CC1=NC=C(C=C)C(CCl)=C1O INXPFKKUKYNUFA-UHFFFAOYSA-N 0.000 description 2
- WWJXFQXQSWAVNC-UHFFFAOYSA-N 5-ethenyl-2-methyl-4-(sulfanylmethyl)pyridin-3-ol;hydrochloride Chemical compound Cl.CC1=NC=C(C=C)C(CS)=C1O WWJXFQXQSWAVNC-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 239000012991 xanthate Substances 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- YYPLPZPLLWYWKD-UHFFFAOYSA-N 2-ethenylpyridin-1-ium;chloride Chemical compound Cl.C=CC1=CC=CC=N1 YYPLPZPLLWYWKD-UHFFFAOYSA-N 0.000 description 1
- OZBBFYJEBDFOCC-UHFFFAOYSA-N 2-methyl-4-(sulfanylmethyl)pyridin-3-ol Chemical compound CC1=NC=CC(=C1O)CS OZBBFYJEBDFOCC-UHFFFAOYSA-N 0.000 description 1
- SGHXCQXVPPRZHT-UHFFFAOYSA-N 2-methyl-5-(2-phenylethenyl)-4-(sulfanylmethyl)pyridin-3-ol;hydrochloride Chemical compound Cl.SCC1=C(O)C(C)=NC=C1C=CC1=CC=CC=C1 SGHXCQXVPPRZHT-UHFFFAOYSA-N 0.000 description 1
- ZHPRHBCYALQKAX-UHFFFAOYSA-N 2-methyl-5-prop-1-enyl-4-(sulfanylmethyl)pyridin-3-ol;hydrochloride Chemical compound Cl.CC=CC1=CN=C(C)C(O)=C1CS ZHPRHBCYALQKAX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- AMVIRXKTLRSLSO-UHFFFAOYSA-N 3-chlorobenzenecarboperoxoic acid;ethaneperoxoic acid Chemical compound CC(=O)OO.OOC(=O)C1=CC=CC(Cl)=C1 AMVIRXKTLRSLSO-UHFFFAOYSA-N 0.000 description 1
- DPZYLEIWHTWHCU-UHFFFAOYSA-N 3-ethenylpyridine Chemical compound C=CC1=CC=CN=C1 DPZYLEIWHTWHCU-UHFFFAOYSA-N 0.000 description 1
- SNGKVTYEWUDNAW-UHFFFAOYSA-N 4-(hydroxymethyl)-2-methyl-5-(2-phenylethenyl)pyridin-3-ol;hydrochloride Chemical compound Cl.OCC1=C(O)C(C)=NC=C1C=CC1=CC=CC=C1 SNGKVTYEWUDNAW-UHFFFAOYSA-N 0.000 description 1
- RPRFHWBZWNZHSW-UHFFFAOYSA-N 4-(hydroxymethyl)-2-methyl-5-prop-1-enylpyridin-3-ol;hydrochloride Chemical compound Cl.CC=CC1=CN=C(C)C(O)=C1CO RPRFHWBZWNZHSW-UHFFFAOYSA-N 0.000 description 1
- OZADGCZKOFJYNG-UHFFFAOYSA-N 5-(2-chloroethenyl)-2-methyl-4-(sulfanylmethyl)pyridin-3-ol;hydrochloride Chemical compound Cl.CC1=NC=C(C=CCl)C(CS)=C1O OZADGCZKOFJYNG-UHFFFAOYSA-N 0.000 description 1
- NLKZCIGBSASFNT-UHFFFAOYSA-N 5-(2-chloroethenyl)-4-(hydroxymethyl)-2-methylpyridin-3-ol;hydrochloride Chemical compound Cl.CC1=NC=C(C=CCl)C(CO)=C1O NLKZCIGBSASFNT-UHFFFAOYSA-N 0.000 description 1
- QQQKOYOXVNFRIN-UHFFFAOYSA-N 5-ethenyl-4-(hydroxymethyl)-2-methylpyridin-3-ol;hydrochloride Chemical compound Cl.CC1=NC=C(C=C)C(CO)=C1O QQQKOYOXVNFRIN-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZCUFTCUMEDALHC-UHFFFAOYSA-N CC[K] Chemical compound CC[K] ZCUFTCUMEDALHC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101000998969 Homo sapiens Inositol-3-phosphate synthase 1 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100036881 Inositol-3-phosphate synthase 1 Human genes 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HVTMBJZAORSECX-UHFFFAOYSA-N OC=1C=NC=C(C=1CS)C=C Chemical compound OC=1C=NC=C(C=1CS)C=C HVTMBJZAORSECX-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- ZFSFDELZPURLKD-UHFFFAOYSA-N azanium;hydroxide;hydrate Chemical compound N.O.O ZFSFDELZPURLKD-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WTEPWWCRWNCUNA-UHFFFAOYSA-M benzyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=CC=CC=C1 WTEPWWCRWNCUNA-UHFFFAOYSA-M 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- GNKXHPULSPWUAK-UHFFFAOYSA-N isopyridoxal Chemical compound CC1=NC=C(C=O)C(CO)=C1O GNKXHPULSPWUAK-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005358 mercaptoalkyl group Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- SJIIDWBFRZACDQ-UHFFFAOYSA-N pyridin-2-ylmethanethiol Chemical compound SCC1=CC=CC=N1 SJIIDWBFRZACDQ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- ADZJWYULTMTLQZ-UHFFFAOYSA-N tritylphosphane;hydrobromide Chemical compound [Br-].C=1C=CC=CC=1C(C=1C=CC=CC=1)([PH3+])C1=CC=CC=C1 ADZJWYULTMTLQZ-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Description
【発明の詳細な説明】
本発明は新規なメルカプトアルキルピリジン誘導体の製
法に関し、更に詳しくはビス〔2−メチル−3−ヒドロ
キシ−5−ビニルピリジル−4−メチル〕ジスルフイド
の製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel mercaptoalkylpyridine derivatives, and more particularly to a method for producing bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide.
本発明の出発化合物は一般に既知のピリジン誘導体より
製する。The starting compounds of the invention are generally prepared from known pyridine derivatives.
6位に遊離のα−メルカプトアルキル基を持ち、α−メ
ルカプトアルキル基がヒドロキシル基に隣)接している
この出発化合物は対応するα−ヒドロキシアルキル化合
物をアルカリ金属ヒドロキサイド(例えば水酸化ナトリ
ウム、水酸化カリウム)を含有する低級アルカノール(
エタノールが良好)中で溶かし、この溶液を二硫化炭素
と反応せしめ、5『C〜還流温度で2〜8時間加熱し、
次に冷却混合物を酸性化する事により容易に製すること
ができる。This starting compound has a free α-mercaptoalkyl group in the 6-position, with the α-mercaptoalkyl group adjacent to the hydroxyl group. lower alkanols (potassium oxide) containing
This solution is reacted with carbon disulfide, heated at 5°C to reflux temperature for 2 to 8 hours,
It can then be easily produced by acidifying the cooled mixture.
単離は濃縮、溶媒抽出の如き基本法で出来る。またピリ
ジン核上の位置にかかわりなく遊離のα−メルカプトア
ルキル基を作る他の方法は前もつて製造したチオ化合物
から保護基を除去する方法で作ることができる。Isolation can be accomplished by basic methods such as concentration and solvent extraction. Another method for producing a free α-mercaptoalkyl group irrespective of its position on the pyridine nucleus is to remove a protecting group from a previously prepared thio compound.
例えばS−ベンゾイルの如きS−アシル化合物は希アル
カリで室温〜75℃でケン化する如き加水分解法により
遊離のメルiカプトに変換される。種々の位置のメルカ
プトアルキル基は又、対応するヒドロキシアルキル基を
チオニルクロライド又は濃臭化水素酸と5『C〜還流温
度で1〜4時間加熱してクロロメチル、又はブロモメチ
ルに変換し、出来たハロメチル基を下記の2種の方法の
いずれかで反応して製することができる。For example, S-acyl compounds such as S-benzoyl are converted to free mercapto by hydrolysis methods such as saponification with dilute alkali at room temperature to 75°C. Mercaptoalkyl groups at various positions can also be prepared by converting the corresponding hydroxyalkyl group to chloromethyl, or bromomethyl, by heating with thionyl chloride or concentrated hydrobromic acid at 5°C to reflux temperature for 1 to 4 hours. It can be produced by reacting a halomethyl group with either of the following two methods.
すなわち(a)水溶液中のノ和メチル化合物をエチルカ
リウムキサントゲネートの如き低級アルキルアルカリ金
属キサントゲネートと5〜10℃で1〜4日間反応せし
め、キサンテート生成物をエーテル等の溶媒で抽出し、
リチウムアルミニウムハイドライド又はナトリウムボロ
ハイドライドで還元する。That is, (a) a methyl compound in an aqueous solution is reacted with a lower alkyl alkali metal xanthogenate such as ethyl potassium xanthogenate at 5 to 10°C for 1 to 4 days, and the xanthate product is extracted with a solvent such as ether. ,
Reduce with lithium aluminum hydride or sodium borohydride.
あるいはまたキサンテートを水酸化カリウ ム又は水酸
化ナトリウムの如きアルコール性アルカリ水溶液と50
℃〜還流温度で加熱せしめ、メルカプトに変える事が出
来る。(b)ハロメチル化合物をメタノール等の低級ア
ルカノール中チオ尿素と50℃一還流温度で1〜4時間
加熱する。Alternatively, the xanthate may be mixed with an aqueous alcoholic alkali solution such as potassium hydroxide or sodium hydroxide for 50 min.
It can be converted to mercapto by heating from °C to reflux temperature. (b) A halomethyl compound is heated with thiourea in a lower alkanol such as methanol at 50°C and reflux temperature for 1 to 4 hours.
次にイソチオウレイドを水又はエタノールの如き低級ア
ルカノール中に水酸化カリウム又は水酸化ナトリウムの
如きアルカリ金属ヒドロキサイドを含ませたものの中で
窒素の如き不活性気体中で50℃〜還流温度に加熱する
。他には、チオウレイドはリチウムアルミニウムハイド
ライド又はリチウムボロハイドライドと前述の如く還元
する。またその製造方法は次の如く示される。The isothioureide is then heated in water or a lower alkanol such as ethanol with an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide under an inert gas such as nitrogen from 50 DEG C. to reflux. Alternatively, thiouraides are reduced with lithium aluminum hydride or lithium borohydride as described above. Further, the manufacturing method thereof is shown as follows.
出発化合物の1つであるメルカブトアルキル化合物のブ
ンテ(Bunte)塩は対応するクロロ一又はブロモメ
チル化合物とナトリウムチオスルフエートとを水性アル
コール中50℃〜環流温度で数分〜2時間加熱して製す
る。One of the starting compounds, the Bunte salt of a mercabutoalkyl compound, is prepared by heating the corresponding chloro-mono- or bromomethyl compound and sodium thiosulfate in aqueous alcohol at 50°C to reflux for several minutes to 2 hours. make
これらのブンテ(Bunte)塩は新しい治療法におい
て有益であり、本発明の対称ジスルフイドへの中間体と
して利用性があるほか、非対称ジスルフイドまたは遊離
のメルカプトメチル化合物への中間体としても利用性が
ある。These Bunte salts are useful in new therapeutics and have utility as intermediates to the symmetric disulfides of the present invention, as well as to asymmetric disulfides or free mercaptomethyl compounds. .
本発明はジスルフイドニ量体のうち特に対称二量体の製
造方法にあり、それらの代表的実際態様は次の通り、(
1)対応する単量体の希水酸化アンモニウム水中に20
〜50℃で15〜30時間空気を導入するか、又は20
−50℃で有機溶媒中1−4日間空気を導入して酸化せ
しめる。The present invention particularly relates to a method for producing a symmetric dimer among disulfide dimers, and typical embodiments thereof are as follows: (
1) 20% of the corresponding monomer in dilute ammonium hydroxide water
Introducing air for 15-30 hours at ~50°C or
Oxidation is carried out in an organic solvent at −50° C. for 1 to 4 days by introducing air.
(2)単量体をm−クロロ過安息香酸過酢酸、過フタル
酸、ナトリウムヒポクロライト、ヨード、過酸化水素の
如き過酸と水溶液中、0−15℃で酸化する。(2) Oxidize the monomer with a peracid such as m-chloroperbenzoic acid peracetic acid, perphthalic acid, sodium hypochlorite, iodine, hydrogen peroxide in aqueous solution at 0-15°C.
(3) ブンテ(Bunte)塩を当量の2−メチル−
3−ヒドロキシ−4−メルカプトメチル−5−ビニルピ
リジンの如きメルカプトメチルピリジンと共に、水酸化
ナトリウム、水酸化カリウムの如きアルカリ金属ヒドロ
キサイド水溶液と20ア−100℃で混合して得る。(3) Bunte salt with an equivalent amount of 2-methyl-
It is obtained by mixing mercaptomethylpyridine such as 3-hydroxy-4-mercaptomethyl-5-vinylpyridine with an aqueous alkali metal hydroxide solution such as sodium hydroxide or potassium hydroxide at 20°C to 100°C.
本発明の方法で得られるジスルフイドは最終生成物のみ
ならず、分子中の他の官能基を扱う間、メルカプト基を
保護する都合のよい手段としてよく用いられる。The disulfide obtained by the process of the invention is often used as a convenient means of protecting the mercapto group while handling other functional groups in the molecule as well as the final product.
この場合単量体は還元して得る。有益な還元系としては
エーテル中リチウムアルミニウムハイドライドと室温で
1〜20時間、塩酸中の匣鉛、酢酸中の岨鉛、塩水中の
スズ等である。最終生成物としても特に有益な保護基と
しても有益である誘導体の他の型は(それらがヒドロキ
シル基にも隣接のヒドロキシメチル、叉はメルカプトメ
チル基にも結合しているからである)環状ケタール又は
アセタールである。これらは例えば3−ヒドロキシ−4
−メルカプトメチル化合物をアセトン又はベンズアルデ
ヒドの如きカルボニル化合物と塩化水素ガスを飽和させ
−5カ−+5℃で2〜6時間反応させて製する。本発明
の化合物は、リウマチ様関節炎用として経口的に、局所
的に、非経口的に、従来の非毒性薬剤的に有益な担体、
賦形薬、補助薬を含む投与単位形で吸入スプレー又は直
腸内に投与できる。In this case, the monomer is obtained by reduction. Useful reducing systems include lithium aluminum hydride in ether for 1 to 20 hours at room temperature, lead in hydrochloric acid, lead in acetic acid, tin in brine, and the like. Other types of derivatives that are particularly useful as final products and as protecting groups (because they are attached to both the hydroxyl group and the adjacent hydroxymethyl or mercaptomethyl group) are cyclic ketals. Or it is an acetal. These are for example 3-hydroxy-4
A -mercaptomethyl compound is prepared by reacting a carbonyl compound such as acetone or benzaldehyde with hydrogen chloride gas at -5°C for 2 to 6 hours at +5°C. The compounds of the present invention can be administered orally, topically, parenterally for use in rheumatoid arthritis, with conventional non-toxic pharmaceutically beneficial carriers,
It can be administered by inhalation spray or rectally in dosage unit form containing excipients and adjuvants.
ここで用いた非経口的という言葉は皮下注射、静脈内、
筋肉内、胸骨内、関節内注射、又は注入法を意味する。
マウス、ラツト、馬、犬、ネコ、等の温血動物の治療用
のほか、本発明の化合物は人間の治療にも効果的である
。例えば一日に体重1キログラムにつき0.5ミリグラ
ム〜140ミリグラムの量の投与が上述の症状の治療に
有効である(患者一日につき25ミリグラム〜7グラム
)。The term parenteral used here refers to subcutaneous injection, intravenous,
Refers to intramuscular, intrasternal, intraarticular injection, or infusion techniques.
In addition to being used in the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the present invention are also effective in the treatment of humans. For example, doses of 0.5 milligrams to 140 milligrams per kilogram of body weight per day are effective in treating the above-mentioned conditions (25 milligrams to 7 grams per patient per day).
例えば炎症は一日に体重1キログラムにつき化合物を0
.1〜50ミリグラム投与すると効果的に治療出来、抗
一発熱、鎮痛効果が明白である。(患者一日につき5ミ
リグラム〜3,5グラム)、一日に体重1キログラムに
つき約1ミリグラム〜約15ミリグラムの投与量で大へ
ん効果的な結果を得る(患者1日につき50ミリグラム
〜1グラム)。単一投与形を作るため担体と合併する活
性成分の量は治療宿主、投与する形態に依存して変化す
る。For example, inflammation requires 0 compounds per kilogram of body weight per day.
.. Administering 1 to 50 milligrams can effectively treat the drug, with obvious antipyretic and analgesic effects. (5 milligrams to 3.5 grams per patient per day), with most effective results obtained at doses of about 1 milligram to about 15 milligrams per kilogram of body weight per day (50 milligrams to 1 gram per kilogram of body weight per patient per day). ). The amount of active ingredient that may be combined with the carrier to produce a single dosage form will vary depending on the host treated and the mode of administration.
例えば人間の経口投与のための剤形は全組成物の5〜9
5パーセントに変化するような適当で都合のよい担体の
量と混合した活性剤、5ミリグラム〜5グラムを含む。
投与単位形は一般に活性成分を25ミリグラム〜500
ミリグラムを含む。しかし多くの患者に対する投与量は
用いた化合物の活性、年令、体重、健康状態、性別、食
事、投与時間、投与経路、排泄速度、併用薬品、治療を
行う病気の程度等に依存する事は理解されよう。次に本
発明の新規化合物の製造を実施例により更に詳しく説明
する。尚原料化合物の製造例を併せて参考例として示す
。実施例 1
ビス〔2−メチル−3−ヒドロキシ−5−ビニル−4−
ピリジルメチル〕ジスルフイド2−メチル−3−ヒドロ
キシ−4−メルカブトメチル一5−ビニルピリジン塩酸
塩(9グラム)を50ミリリツトルの水に溶かし2規定
水酸化アンモニウムで処理してPH9とする。For example, a dosage form for oral administration to humans may contain 5-9% of the total composition.
5 milligrams to 5 grams of active agent mixed with a suitable convenient amount of carrier varying from 5 percent.
Dosage unit forms generally contain between 25 milligrams and 500 milligrams of active ingredient.
Contains milligrams. However, the dosage for most patients depends on the activity of the compound used, age, body weight, health condition, sex, diet, administration time, administration route, excretion rate, concomitant drugs, and the severity of the disease being treated. be understood. Next, the production of the novel compound of the present invention will be explained in more detail with reference to Examples. Note that production examples of raw material compounds are also shown as reference examples. Example 1 Bis[2-methyl-3-hydroxy-5-vinyl-4-
Pyridylmethyl] disulfide 2-methyl-3-hydroxy-4-mercabutomethyl-5-vinylpyridine hydrochloride (9 grams) was dissolved in 50 milliliters of water and treated with 2N ammonium hydroxide to pH 9.
この溶液に24時間空気を導入する。沈澱したビス〔2
−メチル−3−ヒドロキシ−5−ビニル−4−ピリジル
メチル〕ジスルフイドを▲取し乾燥する。融点178−
180ル(分解)。実施例 2
ビス〔2−メチル−3−ヒドロキシ−5−ビニル−4−
ピリジルメチル〕ジスルフイド2−メチル−3−ヒドロ
キシ−4−メルカプトメチル−5−ビニルピリジン塩酸
塩(4.36グラム)を窒素気流下2−7℃で水40ミ
リリツトルに溶かす。Air is introduced into this solution for 24 hours. Precipitated bis [2
-Methyl-3-hydroxy-5-vinyl-4-pyridylmethyl] disulfide is removed and dried. Melting point 178-
180 ru (disassembled). Example 2 Bis[2-methyl-3-hydroxy-5-vinyl-4-
Pyridylmethyl] disulfide 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride (4.36 grams) is dissolved in 40 milliliters of water at 2-7°C under nitrogen flow.
この溶液に2.0ミリリツトルの30パーセント過酸化
水素水を2分以上で加える。この間温度を2−7℃に保
つ。30分間、この温度で攪拌した後、混合物を沢過し
▲液を窒素気流下、過剰の炭酸水素ナトリウム飽和溶液
と2℃で10分間攪拌する。Add 2.0 milliliters of 30 percent hydrogen peroxide to this solution over 2 minutes. During this time the temperature is maintained at 2-7°C. After stirring at this temperature for 30 minutes, the mixture is filtered and the solution ▲ is stirred with excess saturated sodium bicarbonate solution at 2° C. for 10 minutes under a nitrogen stream.
混合物をすばやくp過し、▲過物を2×40ミリリツト
ルのアセトニトリルで洗浄する。固体を五酸化リンで乾
燥して1.5グラムのビス〔2−メチル−3−ヒドロキ
シ−5−ビニルー4−ピリジルメチル〕ジスルフイド、
融点〉300ピを与える。モノハイドレートの融点17
8−180℃o実施例 3
ビス〔2−メチル−3−ヒドロキシ−5−ビニルピリジ
ル−4−メチル〕ジスルフイド2−メチル−3−ヒドロ
キシ−4−メルカプトメチルピリジンのブンテ(Bur
lte)塩(2.6グラム)を10パーセント(W/V
)水酸化ナトリウム水溶液16ミリリツトル中の1.9
グラムの2メチル−3−ヒドロキシ−4−メルカプトメ
チル5−ビニルピリジンの溶液に溶かす。The mixture is quickly filtered and the filtrate washed with 2 x 40 milliliters of acetonitrile. The solid was dried over phosphorous pentoxide to yield 1.5 grams of bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl] disulfide,
Gives a melting point of >300 pi. Melting point of monohydrate 17
Example 3 Bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide 2-methyl-3-hydroxy-4-mercaptomethylpyridine Bur
lte) salt (2.6 grams) at 10 percent (W/V
) 1.9 in 16 ml of sodium hydroxide aqueous solution
grams of 2methyl-3-hydroxy-4-mercaptomethyl 5-vinylpyridine.
希塩酸でPHを6にし、沈澱を▲過して水洗及びアセト
ン、エーテルで洗浄する。これを乾燥しビス〔2−メチ
ル−3−ヒドロキシ−5−ビニルピリジル−4一メチル
〕ジスルフイドを与える。参考例 1
2−メチル−3−ヒドロキシ−4−メルカプトメチル−
5−ビニルピリジン塩酸塩工程A:2−メチル−3−ヒ
ドロキシ−4−ヒドロキシメチル−5−ビニルピリジン
の3・4αジ一0−イソプロピリデン誘導体の作製テト
ラヒドロフラン(300ミリリツトル)中のトリフエニ
ルメチルホスホニウムブロマイド(42.7グラム、0
.12モル)の攪拌懸濁液中に67ミリリツトルのn−
ブチルリチウム(ヘキサン中1.9モル)を窒素気流中
で加える。The pH is adjusted to 6 with dilute hydrochloric acid, and the precipitate is filtered and washed with water, acetone, and ether. This is dried to give bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide. Reference example 1 2-methyl-3-hydroxy-4-mercaptomethyl-
5-Vinylpyridine hydrochloride Step A: Preparation of 3,4α di-10-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine Triphenylmethylphosphonium in tetrahydrofuran (300 milliliters) Bromide (42.7 grams, 0
.. 67 ml of n-
Butyl lithium (1.9 mol in hexane) is added under a stream of nitrogen.
この攪拌溶液にテトラヒドロフラン(300ミリリツト
ル中の2−メチル−3−ヒドロキシ−4−ヒドロキシメ
チル−5−ホルミルピリジン、3・4α−ジ一O−イソ
プロピリデン誘導体(24.7グラム、0.119モル
)の溶液を1時間以上で滴加する。反応を室温で1時間
続け、次に4時間還流する。溶液をまず初めに、ふつう
のポンプ真空下で留去し、次に高真空下30−50℃で
留去乾燥する。赤色油状生成物を400ミリリツトルの
エーテル中にて粉砕し、固体のトリフエニルホスフイン
オキサイドを▲過する(17.0グラム)。エーテル戸
液を2×200ミリリツトルの飽和ナトリウムビサルフ
アイト溶液で抽出する。これを留去乾燥し赤黄色油状物
を得る。生成物を次の工程で用いる。工程B:2−メチ
ル−3−ヒドロキシ−4−ヒドロキシメチル−5−ビニ
ルピリジン塩酸塩の作製上で得た油状物(25グラム、
0.122モル)の溶液を2.5規定塩酸(500ミリ
リツトル)及びアセトン(500ミリリツトル)中で窒
素気流下1.5時間、攪拌還流を行う。To this stirred solution was added tetrahydrofuran (2-methyl-3-hydroxy-4-hydroxymethyl-5-formylpyridine, 3,4α-di-O-isopropylidene derivative (24.7 grams, 0.119 mol) in 300 milliliters). is added dropwise over 1 hour. The reaction is continued for 1 hour at room temperature and then refluxed for 4 hours. The solution is first distilled off under normal pump vacuum and then under high vacuum at 30-50 °C. Evaporate to dryness at °C. The red oil product is triturated in 400 milliliters of ether and filtered to remove solid triphenylphosphine oxide (17.0 grams). The ether solution is diluted with 2 x 200 milliliters of saturation. Extract with sodium bisulfite solution. This is evaporated to dryness to give a red-yellow oil. The product is used in the next step. Step B: 2-Methyl-3-hydroxy-4-hydroxymethyl-5-vinyl The oil obtained in the preparation of pyridine hydrochloride (25 grams,
A solution of 0.122 mol) was stirred and refluxed in 2.5N hydrochloric acid (500 ml) and acetone (500 ml) under a nitrogen atmosphere for 1.5 hours.
アセトンを留去して90℃にまでし、溶液を冷却し酢酸
エチル(3×400ミリリツトル)で抽出する。水層を
過剰の飽和炭酸水素ナトリウム溶液(700ミリリツト
ル)中に注入する。水層を酢酸エチル(1×400ミリ
リツトル)で抽出する。The acetone is distilled off to 90° C., the solution is cooled and extracted with ethyl acetate (3×400 milliliters). The aqueous layer is poured into excess saturated sodium bicarbonate solution (700 milliliters). The aqueous layer is extracted with ethyl acetate (1 x 400 milliliters).
有機溶媒を乾燥(MgSO4)し、▲過、留去して酢酸
エチルで再結晶して無色結晶を与える。融点164−1
66結、9.4グラム。工程C:2−メチル−3−ヒド
ロキシ−4−メルカプトメチル−5−ビニルピリジン塩
酸塩の作製窒素ガス導入管、温度計、コンデンサーの上
部に滴加ロードを付けた1リツトルの3径フラスコに9
0パーセントエタノール530ミリリツトル、NaOH
53.4グラムを加える。The organic solvent is dried (MgSO4), filtered and evaporated, and recrystallized from ethyl acetate to give colorless crystals. Melting point 164-1
66 knots, 9.4 grams. Step C: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride Into a 1-liter 3-diameter flask equipped with a nitrogen gas introduction tube, a thermometer, and a dropping load on the top of the condenser,
0% ethanol 530ml, NaOH
Add 53.4 grams.
溶液が出来たら、工程Bの生成物50グラムを加える。
この溶液に(N2ガス下)10−15をで攪拌下1/2
時間以上かけて、30ミリリツトルのCS2を滴加する
。出米た混合物を、次に20℃で1/2時間攪拌し、次
に15℃に冷却しさらにCS22Oミリリツトルを滴加
して4時間還流する。次に混合物を1『Cに冷却しPH
が2になるまで濃塩酸を加える(約80ミリリツトル必
要)。混合物を氷浴中で一夜放置する。減圧下濃縮し(
浴温20氷)エタノールを除去する。出来た物質を1リ
ツトルの水と120グラムのNaHCO3の冷却攪拌懸
濁液に(N2ガス下)加える。有機物を3×300ミリ
リツトルの酢酸エチルで抽出する(出米るだけ空気を除
外する)。合併した抽出液をMgSO4で乾燥する。こ
れを▲過し、減圧濃縮する。残渣を約1キログラムのS
iO2(Baker)と溶出液として酢酸エチルを用い
てクロマトグラフイ一を行い精製する。対応する分画(
Tlc−EtOAc展開により決定)を合併し適当な量
にまで濃縮し白色結晶の遊離塩基を与える。最初の収獲
物融点115一117塩(33グラム)、第2収獲物、
融点114−116グ(6グラム)元素分析 C9Hl
lNOSとして、
計算値:Cl59.66:Hl6.l2:Nl7.33
;Sll7,7実測値:Cl59.64;Hl6.35
;Nl7.26:Sll7.3Oこれを次の方法で塩酸
塩に変える。Once the solution is formed, add 50 grams of the product from Step B.
To this solution (under N2 gas) add 10-15 liters of water under stirring.
Add 30 milliliters of CS2 dropwise over a period of time. The resulting mixture is then stirred at 20° C. for 1/2 hour, then cooled to 15° C. and further milliliters of CS22O are added dropwise and refluxed for 4 hours. The mixture was then cooled to 1'C and the pH
Add concentrated hydrochloric acid until the value reaches 2 (about 80 ml is required). Leave the mixture in an ice bath overnight. Concentrate under reduced pressure (
Bath temperature 20 ice) Remove ethanol. The resulting material is added (under N2 gas) to a cooled stirred suspension of 1 liter of water and 120 grams of NaHCO3. Extract the organic matter with 3 x 300 milliliters of ethyl acetate (excluding as much air as possible). The combined extracts are dried with MgSO4. This is filtered and concentrated under reduced pressure. Approximately 1 kg of the residue
Purification is performed by chromatography using iO2 (Baker) and ethyl acetate as the eluent. The corresponding fraction (
(determined by Tlc-EtOAc evolution) and concentrated to the appropriate volume to give the free base as white crystals. First harvest melting point 115-117 salt (33 grams), second harvest,
Melting point 114-116g (6 grams) Elemental analysis C9Hl
As INOS, calculated value: Cl59.66:Hl6. l2:Nl7.33
; Sll7,7 actual value: Cl59.64; Hl6.35
;Nl7.26:Sll7.3O This is converted into hydrochloride by the following method.
遊離塩基(39グラム)を500ミリリツトルの乾燥T
HF′に溶かし、攪拌下、乾燥HClガスを25℃以下
に保ちながら、わずかに過剰になるまで導入する。Free base (39 grams) in 500 milliliters of dry T.
Dissolve in HF' and introduce dry HCl gas under stirring, keeping the temperature below 25° C., until there is a slight excess.
出来た白色沈澱をr取し、テトラヒドロフランで洗浄し
真空下乾燥する。融点149152℃、Wt45グラム
。元素分析 C9Hl2ClNOSとして、分子量21
7.7計算値:Cl49.65:Hl5.56:Nl6
,44;Sll4.73実測値:Cl49.87:Hl
5.82;Nl6.44;Sll5.lO参考例1で述
べた方法と本質的に同様な方法を用い、ここで用いた工
程Aにおけるトリフエニルメチルホスホニウムブロマイ
ドの代りに当量のトリフエニルエチルホスホニウムブロ
マイド、トリフエニルベンジルホスホニウムブロマイド
、及びトリフエニルクロロメチルホスホニウムブロマイ
ド等を用いて、それぞれ連続に製する。The white precipitate formed is collected, washed with tetrahydrofuran, and dried under vacuum. Melting point: 149,152°C, Wt: 45 grams. Elemental analysis As C9Hl2ClNOS, molecular weight 21
7.7 Calculated value: Cl49.65: Hl5.56: Nl6
, 44; Sll4.73 actual value: Cl49.87:Hl
5.82;Nl6.44;Sll5. IO Using a method essentially similar to that described in Reference Example 1, instead of triphenylmethylphosphonium bromide in Step A used here, equivalent amounts of triphenylethylphosphonium bromide, triphenylbenzylphosphonium bromide, and triphenyl Each is produced continuously using chloromethylphosphonium bromide or the like.
工程A:2−メチル−3−ヒドロキシ−4−ヒドロキシ
メチル−5−(1−プロベニル)−ピリジンの3・4α
−ジ一0−イソプロピリデン誘導体(油状物、35パー
セント収率);2−メチル−3−ヒドロキシ−4−ヒド
ロキシメチル−5−スチリルピリジンの3・4α−ジ一
0−イソプロピリデン誘導体。Step A: 3.4α of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-probenyl)-pyridine
- Di10-isopropylidene derivative (oil, 35 percent yield); 3,4α-di10-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-styrylpyridine.
及び2−メチル−3−ヒドロキシ−4−ヒドロキシメチ
ル−5−(2−クロロビニル)ピリジンの3・4α−ジ
一0−イソプロピリデン誘導体。and 3,4α-di-10-isopropylidene derivatives of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)pyridine.
工程B:2−メチル−3−ヒドロキシ−4−ヒドロキシ
メチル−5−(1−プロペニル)−ピリジン塩酸塩(1
00パーセント収率)2−メチル−3−ヒドロキシ−4
−ヒドロキシメチル−5−スチリルピリジン塩酸塩;及
び2−メチル−3−ヒドロキシ−4−ヒドロキシメチル
−5−(2−クロロビニル)ピリジン塩酸塩。Step B: 2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-propenyl)-pyridine hydrochloride (1
00 percent yield) 2-methyl-3-hydroxy-4
-hydroxymethyl-5-styrylpyridine hydrochloride; and 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)pyridine hydrochloride.
工程C:2−メチル−3−ヒドロキシ−4−メルカプト
メチル−5−(−プロペニル)ピリジン塩酸塩(60パ
ーセント収率、融点175ジ178℃)2−メチル−3
−ヒドロキシ−4−メルカプトメチル−5−スチリルピ
リジン塩酸塩(融点190−195℃);及び2−メチ
ル−3−ヒドロキシ−4−メルカプトメチル−5−(2
−クロロビニル)ピリジン塩酸塩。Step C: 2-Methyl-3-hydroxy-4-mercaptomethyl-5-(-propenyl)pyridine hydrochloride (60 percent yield, mp 175°C) 2-methyl-3
-hydroxy-4-mercaptomethyl-5-styrylpyridine hydrochloride (melting point 190-195°C); and 2-methyl-3-hydroxy-4-mercaptomethyl-5-(2
-chlorovinyl)pyridine hydrochloride.
参考例 2
2−メチル−3−ヒドロキシ−4−メルカプトメチル−
5−ビニルピリジンのブンテ(Bunte)塩工程A:
2−メチル−3−ヒドロキシ−4−クロロメチル−5−
ビニルピリジン塩酸塩の作製1.65グラムの2−メチ
ル−3−ヒドロキシ−4−ヒドロキシメチル−5−ビニ
ルピリジン塩酸塩、1ミリリツトルのチオニルクロライ
ド、20ミリリツトルのテトラヒドロフランの混合物を
6時間還流する。Reference example 2 2-methyl-3-hydroxy-4-mercaptomethyl-
Bunte salt of 5-vinylpyridine Step A:
2-Methyl-3-hydroxy-4-chloromethyl-5-
Preparation of Vinylpyridine Hydrochloride A mixture of 1.65 grams of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride, 1 milliliter of thionyl chloride, and 20 milliliters of tetrahydrofuran is refluxed for 6 hours.
冷却沈澱を▲取しエーテルで洗浄し乾燥して2−メチル
−3−ヒドロキシ−4−クロロメチル−5−ビニルピリ
ジン塩酸塩を与える。工程B:2−メチル−3−ヒドロ
キシ−4−メルカプトメチル−5−ビニルピリジンのブ
ンテ(BU]1te)塩の作製20グラムのナトリウム
チオスルフエート5水和物の15ミリリツトル水溶液を
18グラムの2一メチル一3−ヒドロキシ−4−クロロ
メチル−5−ビニルピリジン塩酸塩の50パーセントエ
タノール100ミリリツトル溶液に加える。The cooled precipitate is collected, washed with ether and dried to give 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride. Step B: Preparation of Bunte (BU]1te) salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. Add to a solution of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride in 100 milliliters of 50 percent ethanol.
混合物を1時間75℃に加熱し、冷却、溶媒留去して乾
燥し、2−メチル−3−ヒドロキシ−4−メルカプトメ
チル−5−ビニルピリジンのブンテ(Bullte)塩
融点198−200℃を与える。The mixture is heated to 75°C for 1 hour, cooled and evaporated to dryness to give the Bullte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, mp 198-200°C. .
Claims (1)
▲数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。 2 下記式: ▲数式、化学式、表等があります▼ の化合物と酸化剤とを反応せしめることを特徴とする式
:▲数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。 3 下記式: ▲数式、化学式、表等があります▼ の化合物を式: ▲数式、化学式、表等があります▼ とアルカリ性溶液中で加熱することを特徴とする式:▲
数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。[Claims] 1. A formula characterized by exposing a compound of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to air or oxygen:
▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing the compound or its pharmaceutically effective salt. 2 The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A formula characterized by reacting the compound of ▼ with an oxidizing agent: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound or its pharmaceutically effective salt manufacturing method. 3 The formula below: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound of: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and the formula characterized by heating in an alkaline solution: ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Process for producing the compound or its pharmaceutically effective salt.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36877273A | 1973-06-15 | 1973-06-15 | |
US46177874A | 1974-04-18 | 1974-04-18 | |
US46401174A | 1974-04-26 | 1974-04-26 |
Publications (2)
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---|---|
JPS5040574A JPS5040574A (en) | 1975-04-14 |
JPS59511B2 true JPS59511B2 (en) | 1984-01-07 |
Family
ID=27408882
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JP49067656A Expired JPS59511B2 (en) | 1973-06-15 | 1974-06-15 | Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide |
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CA (1) | CA1021342A (en) |
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DE (1) | DE2428470A1 (en) |
DK (1) | DK148594C (en) |
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ES (1) | ES427187A1 (en) |
FI (1) | FI167474A (en) |
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GB (1) | GB1473591A (en) |
IE (1) | IE39896B1 (en) |
IL (1) | IL44958A (en) |
LU (1) | LU70318A1 (en) |
NL (1) | NL187395C (en) |
NO (1) | NO144569C (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3290319A (en) * | 1965-02-26 | 1966-12-06 | Bristol Myers Co | Substituted carbamates of pyridine 2, 6-dimethanethiols |
US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
DE2161403A1 (en) * | 1970-12-17 | 1972-07-06 | Hidaka, Hiroyoshi, Nagoya, Aichi (Japan) | Pyridine carbamate derivatives and processes for making the same |
-
1974
- 1974-05-27 SE SE7406972A patent/SE411208B/en not_active IP Right Cessation
- 1974-05-29 NL NLAANVRAGE7407212,A patent/NL187395C/en not_active IP Right Cessation
- 1974-05-29 DK DK290274A patent/DK148594C/en not_active IP Right Cessation
- 1974-05-30 NO NO741962A patent/NO144569C/en unknown
- 1974-05-31 FI FI1674/74*#A patent/FI167474A/fi unknown
- 1974-06-03 IL IL44958A patent/IL44958A/en unknown
- 1974-06-11 GB GB2585874A patent/GB1473591A/en not_active Expired
- 1974-06-11 ES ES427187A patent/ES427187A1/en not_active Expired
- 1974-06-11 IE IE1220/74A patent/IE39896B1/en unknown
- 1974-06-12 FR FR7420305A patent/FR2233055B1/fr not_active Expired
- 1974-06-12 DE DE19742428470 patent/DE2428470A1/en active Granted
- 1974-06-12 ZM ZM92/74A patent/ZM9274A1/en unknown
- 1974-06-13 LU LU70318A patent/LU70318A1/xx unknown
- 1974-06-14 CH CH822074A patent/CH605764A5/xx not_active IP Right Cessation
- 1974-06-14 CA CA202,690A patent/CA1021342A/en not_active Expired
- 1974-06-15 JP JP49067656A patent/JPS59511B2/en not_active Expired
- 1974-06-15 EG EG226/74A patent/EG11578A/en active
-
1977
- 1977-10-06 SE SE7711211A patent/SE426170B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
DK148594C (en) | 1986-01-27 |
GB1473591A (en) | 1977-05-18 |
CA1021342A (en) | 1977-11-22 |
IL44958A (en) | 1978-09-29 |
DK290274A (en) | 1975-02-10 |
FR2233055A1 (en) | 1975-01-10 |
NL187395B (en) | 1991-04-16 |
IL44958A0 (en) | 1974-09-10 |
SE411208B (en) | 1979-12-10 |
ZM9274A1 (en) | 1976-02-23 |
FI167474A (en) | 1974-12-16 |
NO144569C (en) | 1981-09-23 |
CH605764A5 (en) | 1978-10-13 |
AU6976574A (en) | 1975-12-04 |
DE2428470A1 (en) | 1975-01-23 |
NO144569B (en) | 1981-06-15 |
DK148594B (en) | 1985-08-12 |
IE39896B1 (en) | 1979-01-31 |
FR2233055B1 (en) | 1977-11-04 |
SE7711211L (en) | 1977-10-06 |
DE2428470C2 (en) | 1988-10-13 |
NL187395C (en) | 1991-09-16 |
LU70318A1 (en) | 1975-03-06 |
JPS5040574A (en) | 1975-04-14 |
ES427187A1 (en) | 1977-01-01 |
IE39896L (en) | 1974-12-15 |
EG11578A (en) | 1978-03-29 |
SE426170B (en) | 1982-12-13 |
SE7406972L (en) | 1974-12-16 |
NL7407212A (en) | 1974-12-17 |
NO741962L (en) | 1975-01-13 |
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